Antibody-based immunotherapy for ovarian cancer: where are we at?

Cytoreductive surgery and chemotherapy continue to be the mainstay of ovarian cancer treatment. However, as mortality from advanced ovarian cancer remains very high, novel therapies are required to be integrated into existing treatment regimens. Immunotherapy represents an alternative and rational therapeutic approach for ovarian cancer based on a body of evidence supporting a protective role of the immune system against these cancers, and on the clinical success of immunotherapy in other malignancies. Whether or not immunotherapy will have a role in the future management of ovarian cancer is too early to tell, but research in this field is active. This review will discuss recent clinical developments of selected immunotherapies for ovarian cancer which fulfil the following criteria: (i) they are antibody-based, (ii) target a distinct immunological pathway, and (iii) have reached the clinical trial stage. Specifically, the focus is on Catumaxomab (anti-EpCAM × anti-CD3), Abagovomab, Oregovomab (anti-CA125), Daclizumab (anti-CD25), Ipilimumab (anti-CTLA-4), and MXD-1105 (anti-PD-L1). Catumaxomab has reached phase III clinical trials and exhibits promise with reports, showing that it can cause a significant and sustained reduction in ascites. Phase I-III clinical trials continue to be conducted on the other antibodies, some of which have had encouraging reports. We will also provide our perspective on the future of immunotherapy for ovarian cancer, and how it may be best employed in treatment regimen

The optical system of the H.E.S.S. imaging atmospheric Cherenkov telescopes, Part II: mirror alignment and point spread function

Mirror facets of the H.E.S.S. imaging atmospheric Cherenkov telescopes are aligned using stars imaged onto the closed lid of the PMT camera, viewed by a CCD camera. The alignment procedure works reliably and includes the automatic analysis of CCD images and control of the facet alignment actuators. On-axis, 80% of the reflected light is contained in a circle of less than 1 mrad diameter. The spot widens with increasing angle to the telescope axis. In accordance with simulations, the spot size has roughly doubled at an angle of 1.4 degr. from the axis. The expected variation of spot size with elevation due to deformations of the support structure is visible, but is completely non-critical over the usual working range. Overall, the optical quality of the telescope exceeds the specifications.Comment: 23 pages, 13 figure

An unidentified TeV source in the vicinity of Cygnus OB2

Deep observation (∼113 hrs) of the Cygnus region at TeV energies using the HEGRA stereoscopic system of air Čerenkov telescopes has serendipitously revealed a signal positionally inside the core of the OB association Cygnus OB2, at the edge of the 95% error circle of the EGRET source 3EG J2033+4118, and ∼0.5° north of Cyg X-3. The source centre of gravity is RA αJ2000: 20hr32m07s± 9.2stats±2.2syss, Dec δJ2000: +41°30′30″2.0stat±0.4′sys. The source is steady, has a post-trial significance of +4.6σ, indication for extension with radius 5.6′ at the ∼3σ level, and has a differential power-law flux with hard photon index of - 1.9 ± 0.3stat ± 0.3sys. The integral flux above 1 TeV amounts ∼3% that of the Crab. No counterpart for the TeV source at other wavelengths is presently identified, and its extension would disfavour an exclusive pulsar or AGN origin. If associated with Cygnus OB2, this dense concentration of young, massive stars provides an environment conducive to multi-TeV particle acceleration and likely subsequent interaction with a nearby gas cloud. Alternatively, one could envisage γ-ray production via a jet-driven termination shock.F. A. Aharonian, ... G. P. Rowell, ... [et al

5PMICROTUBULE-DEPOLYMERIZING AGENTS USED IN ANTIBODY-DRUG-CONJUGATES INDUCE ANTITUMOR ACTIVITY BY STIMULATION OF DENDRITIC CELLS

Antibody drug conjugates (ADCs) are emerging as powerful treatment strategies with outstanding target specificity and high therapeutic activity in cancer patients. While >30 ADCs are currently being investigated in clinical trials, brentuximabvedotin and T-DM1 represent clinically approved ADCs in cancer patients. We hypothesized that their sustained clinical responses could be related to the stimulation of an antitumor immune response. Indeed, the two microtubule-destabilizing agents Dolastatin 10 and Ansamitocin P3, from which the cytotoxic components of brentuximabvedotin and T-DM1 are derived, may serve as prototypes for a class of agents that induce tumor cell death and convert tumor resident, tolerogenic dendritic cells (DCs) into efficient antigen presenting cells (APCs). The two drugs induced phenotypic and functional maturation of murine splenic as well as human monocyte-derived DCs. In contrast, microtubule-stabilizing agents such as taxanes did not display this feature. In tumor models, both Dolastatin 10 and Ansamitocin P3 efficiently promoted antigen uptake and migration of tumor-resident DCs to tumor-draining lymph nodes, thereby potentiating tumor-specific T cell responses. Underlining the requirement of an intact host immune system for the full therapeutic benefit of these two compounds, their antitumor effect was far less pronounced in mice lacking adaptive immunity or dendritic cells. Combinations with immune checkpoint inhibition (anti-CTLA-4/-PD-1) did further augment antitumor immunity and tumor rejection, which was reflected by reduced Treg numbers and elevated effector function of tumor resident T cells. Ultimately, we were able to demonstrate peripheral immune cell activation and brisk T cell infiltration into tumors in patients previously treated with BrentuximabVedotin. Experiments are currently ongoing to investigate the immunological mode of action of T-DM1 using orthotopic breast cancer models and patients undergoing treatment. Our data reveal a novel mode of action for microtubule-depolymerizing agents and provide a strong rationale for clinical treatment regimens combining these with immune-based therapies. Disclosure: All authors have declared no conflicts of interes

The unidentified TeV source (TeVJ2032+4130) and surrounding field: Final HEGRA IACT-System results

The unidentified TeV source in Cygnus is now confirmed by follow-up observations from 2002 with the HEGRA stereoscopic system of Cherenkov Telescopes. Using all data (1999 to 2002) we confirm this new source as steady in flux over the four years of data taking, extended with radius 6.2 arcmin (+-1.2 arcmin (stat) +-0.9 arcmin (sys)) and exhibiting a hard spectrum with photon index -1.9. It is located in the direction of the dense OB stellar association, Cygnus OB2. Its integral flux above energies E>1 TeV amounts to \~5% of the Crab assuming a Gaussian profile for the intrinsic source morphology. There is no obvious counterpart at radio, optical nor X-ray energies, leaving TeVJ2032+4130 presently unidentified. Observational parameters of this source are updated here and some astrophysical discussion is provided. Also included are upper limits for a number of other interesting sources in the FoV, including the famous microquasar Cygnus X-3.Comment: 7 pages, 3 figures. Accepted for publication in Astronomy & Astrophysic

Simultaneous X-Ray and TeV Gamma-Ray Observations of the TeV Blazar Markarian 421 during February and May 2000

In this paper we present the results of simultaneous observations of the TeV blazar Markarian 421 (Mrk 421) at X-ray and TeV Gamma-ray energies with the Rossi X-Ray Timing Explorer (RXTE) and the stereoscopic Cherenkov Telescope system of the HEGRA (High Energy Gamma Ray Astronomy) experiment, respectively. The source was monitored from February 2nd to February 16th and from May 3rd to May 8th, 2000. We discuss in detail the temporal and spectral properties of the source. Remarkably, the TeV observations of February 7th/8th showed statistically significant evidence for substantial TeV flux variability on 30 min time scale. We show the results of modeling the data with a time dependent homogeneous Synchrotron Self-Compton (SSC) model. The X-ray and TeV gamma-ray emission strengths and energy spectra together with the rapid flux variability strongly suggest that the emission volume is approaching the observer with a Doppler factor of 50 or higher. The different flux variability time scales observed at X-rays and TeV Gamma-rays indicate that a more detailed analysis will require inhomogeneous models with several emission zones.Comment: Accepted for Publication in ApJ, 21 Pages, 5 Figure

Intention to Inform Relatives, Rates of Cascade Testing, and Preference for Patient-Mediated Communication in Families Concerned with Hereditary Breast and Ovarian Cancer and Lynch Syndrome: The Swiss CASCADE Cohort.

Cascade screening for Tier 1 cancer genetic conditions is a significant public health intervention because it identifies untested relatives of individuals known to carry pathogenic variants associated with hereditary breast and ovarian cancer (HBOC) and Lynch syndrome (LS). The Swiss CASCADE is a family-based, open-ended cohort, including carriers of HBOC- and LS-associated pathogenic variants and their relatives. This paper describes rates of cascade screening in relatives from HBOC- and LS- harboring families, examines carriers' preferences for communication of testing results, and describes theory-based predictors of intention to invite relatives to a cascade screening program. Information has been provided by 304 index cases and 115 relatives recruited from September 2017 to December 2021. On average, 10 relatives per index case were potentially eligible for cascade screening. Approximately 65% of respondents wanted to invite relatives to the cohort, and approximately 50% indicated a preference for patient-mediated communication of testing results, possibly with the assistance of digital technology. Intention to invite relatives was higher for first- compared to second- and third-degree relatives, but was not different between syndromes or based on relatives' gender. The family environment and carrying pathogenic variants predicts intention to invite relatives. Information helps optimize delivery of tailored genetic services

Rejection of the hypothesis that Markarian 501 TeV photons are pure Bose-Einstein condensates

The energy spectrum of the Blazar type galaxy Markarian 501 (Mrk 501) as measured by the High-Energy-Gamma-Ray Astronomy (HEGRA) air Cerenkov telescopes extends beyond 16 TeV and constitutes the most energetic photons observed from an extragalactic object. A fraction of the emitted spectrum is possibly absorbed in interactions with low energy photons of the diffuse extragalactic infrared radiation, which in turn offers the unique possibility to measure the diffuse infrared radiation density by TeV spectroscopy. The upper limit on the density of the extragalactic infrared radiation derived from the TeV observations imposes constraints on models of galaxy formation and stellar evolution. One of the recently published ideas to overcome severe absorption of TeV photons is based upon the assumption that sources like Mrk 501 could produce Bose-Einstein condensates of coherent photons. The condensates would have a higher survival probability during the transport in the diffuse radiation field and could mimic TeV air shower events. The powerful stereoscopic technique of the HEGRA air Cerenkov telescopes allows to test this hypothesis by reconstructing the penetration depths of TeV air shower events: Air showers initiated by Bose-Einstein condensates are expected to reach the maximum of the shower development in the atmosphere earlier than single photon events. By comparing the energy-dependent penetration depths of TeV photons from Mrk 501 with those from the TeV standard-candle Crab Nebula and simulated air shower events, we can reject the hypothesis that TeV photons from Mrk 501 are pure Bose-Einstein condensates.Comment: 9 pages, 2 figures, published by ApJ Letters, revised version (simulation results added

Correlated intense X-ray and TeV activity of Mrk~501 in 1998 June

We present exactly simultaneous X-ray and TeV monitoring with {\it RXTE} and HEGRA of the TeV blazar Mrk 501 during 15 days in 1998 June. After an initial period of very low flux at both wavelengths, the source underwent a remarkable flare in the TeV and X-ray energy bands, lasting for about six days and with a larger amplitude at TeV energies than in the X-ray band. At the peak of the TeV flare, rapid TeV flux variability on sub-hour timescales is found. Large spectral variations are observed at X-rays, with the 3--20 keV photon index of a pure power law continuum flattening from $\Gamma=2.3$ to $\Gamma=1.8$ on a timescale of 2--3 days. This implies that during the maximum of the TeV activity, the synchrotron peak shifted to energies $\gtrsim 50$ keV, a behavior similar to that observed during the longer-lasting, more intense flare in 1997 April. The TeV spectrum during the flare is described by a power law with photon index $\Gamma=1.9$ and an exponential cutoff at $\sim$ 4 TeV; an indication for spectral softening during the flare decay is observed in the TeV hardness ratios. Our results generally support a scenario where the TeV photons are emitted via inverse Compton scattering of ambient seed photons by the same electron population responsible for the synchrotron X-rays. The simultaneous spectral energy distributions (SEDs) can be fit with a one-zone synchrotron-self Compton model assuming a substantial increase of the magnetic field and the electron energy by a factor of 3 and 10, respectively.Comment: Accepted for publication in ApJ, Part

The TeV Energy Spectrum of Mkn 501 Measured with the Stereoscopic Telescope System of HEGRA during 1998 and 1999

During 1997, the BL Lac object Mkn 501 went into an extraordinary state of high X-ray and TeV gamma-ray activity, lasting more than 6 months. In this paper we report on the TeV emission characteristics of the source in the subsequent years of 1998 and 1999 as measured with the Stereoscopic Cherenkov Telescope System of HEGRA (La Palma, Canary Islands). Our observations reveal a 1998-1999 mean emission level at 1 TeV of 1/3 of the flux of the Crab Nebula, a factor of 10 lower than during the year of 1997. A dataset of 122 observations hours with the HEGRA telescope system makes it possible to assess for the first time the Mkn 501 TeV energy spectrum for a mean flux level substantially below that of the Crab Nebula with reasonable statistical accuracy. Excluding the data of a strong flare, we find evidence that the 1998--1999 low-flux spectrum is substantially softer (by 0.44+-0.1(stat) in spectral index) than the 1997 time averaged spectrum. The 500 GeV to 10 TeV energy spectrum can well be described by a power law model with exponential cutoff: dN/dE ~ E^(-alpha) exp(-E/E0) with alpha=2.31+-0.22(stat), and E0=5.1 (-2.3+7.8)(stat) TeV. Within statistical accuracy, also a pure power law model gives an acceptable fit to the data: dN/dE ~ E^(-Gamma) with Gamma=2.76+-0.08(stat). After presenting the 1998-1999 TeV characteristics of the source we discuss the implications of the results.Comment: Accepted for publication in The Astrophysical Journal, Part 1, on August 4th, 200